Alzheimer's disease (AD) is the most prevalent form of dementia characterized by progressive memory deterioration, diminished cognitive function, and altered behavior afflicting nearly 50% of individuals 85 years and older. AD-related pathologies evolve in a temporal and spatial manner as evidenced by A2 peptide deposition, neurofibrillary tangle formation, decreased synaptic integrity, and neuronal loss. Although the etiology of AD is unknown, overwhelming data support inflammation as being a major player influencing the development and severity of these cardinal pathologies, as extensive production of cytokines and other inflammatory molecules and the activation of microglia have been implicated in the disease process. Our laboratory is interested in dissecting the inflammatory signaling cascades active during the early pre- symptomatic stages of AD, as insight into these processes may facilitate the development of therapeutic strategies that are truly disease ameliorating. Our laboratory utilizes the 3xTg-AD mouse model of AD, which exhibits plaque and tau pathology in a progressive and age-dependent manner and to date, is the most representative mouse model of human AD. We have previously shown that the potent pro-inflammatory molecule, tumor necrosis factor-alpha (TNF-1), is up-regulated in 3xTg-AD mice at ages preceding the development of hallmark amyloid and tau pathologies (Janelsins et al., 2005), and that chronic expression of this cytokine in 3xTg-AD mice leads to marked neuronal death (Janelsins et al., 2008). Although much is known about TNF- function and signaling in peripheral immune responses, the relative brain-specific contributions of each cognate receptor of TNF- , TNF-RI and TNF-RII, to the downstream pathogenic signaling cascades in AD are presently unknown. We hypothesize that selective abrogation of TNF- receptor expression at a pre-pathologic stage and in the context of established disease will differentially impact the severity of amyloid and tau pathologies and associated neuroinflammation in Alzheimer's disease. We intend to employ two strategies to test this hypothesis: (1) 3xTgAD mice lacking TNF-RI and TNF-RII have been created to study the effects global ablation of TNF- receptor expression has on pathological progression;and (2) small inhibitory RNA's (siRNA's) have been designed, tested, and engineered into adeno-associated virus (AAV) vector to selectively and chronically knock down TNF-RI or RII expression in vivo to dissect the disease stage-specific role of TNF-1 signaling during AD pathogenesis. PUBLIC HEALTH RELEVANCE: Alzheimer's Disease (AD) is the most common age-related neurodegenerative disorder affecting approximately 20 percent of individuals over age 80 and approximately 40 percent of those over age 85. Approximately fifty percent of nursing home residents in the United States are affected by AD contributing to an annual cumulative cost exceeding 65 billion dollars. As the population ages, the incidence of AD will increase dramatically, and by 2050 it is estimated that between 11 and 16 million Americans will be living with AD, making research in diagnosis, treatment, and prevention of this devastating disease a matter of great national importance.